Rafael Sivera1, Vincenzo Lupo2, Marina Frasquet3,4,5, Herminia Argente-Escrig3,4,5, Jorge Alonso-Pérez6,7, Jordi Díaz-Manera5,6,7,8, Luis Querol5,6,7, María Del Mar García-Romero9,10, Samuel Ignacio Pascual9,10, Tania García-Sobrino11, Carmen Paradas12,13, Juan Francisco Vázquez-Costa3,4,5,14, Nuria Muelas3,4,5, Elvira Millet15, Juan Jesús Vílchez3,4,5,14, Carmen Espinós2, Teresa Sevilla3,4,5,14. 1. Department of Neurology, Hospital Francesc de Borja, Gandía, Spain. 2. Unit of Rare Neurodegenerative Diseases Felipe, Centro de Investigación Príncipe, Valencia, Spain. 3. Neuromuscular Diseases Unit, Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain. 4. Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain. 5. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. 6. Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 7. Universitat Autonoma de Barcelona, Barcelona, Spain. 8. John Walton Muscular Dystrophy Research Center, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, UK. 9. Neuropaediatrics Department, Hospital Universitario La Paz, Madrid, Spain. 10. Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain. 11. Department of Neurology, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain. 12. Department of Neurology, Hospital Universitario Virgen del Rocío, Sevilla, Spain. 13. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. 14. Department of Medicine, Universitat de València, Valencia, Spain. 15. Neuromuscular Diseases Unit, Department of Clinical Neurophysiology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
Abstract
BACKGROUND AND PURPOSE: MORC2 mutations have been described as a rare cause of axonal Charcot-Marie-Tooth disease (CMT2Z). The aim of this work was to determine the frequency and distribution of these mutations throughout Spain, to provide a comprehensive phenotypical description and, if possible, to establish a genotype-phenotype correlation. METHODS: Retrospectively, data on patients diagnosed with CMT2Z in Spain were collected and clinical, electrophysiological and muscle imaging information were analysed. RESULTS: Fifteen patients with CMT2Z were identified throughout Spain, seven of them belonging to a single kindred, whilst the rest were sporadic. The most common mutation was p.R252W, and four new mutations were identified. Eleven patients were categorized as having a scapuloperoneal phenotype, with asymmetric muscle weakness, early proximal upper limb involvement and frequent spontaneous muscular activity with distal sensory impairment and pes cavus, whilst two presented with a more classic length dependent sensory motor phenotype. This distinction was corroborated by the distribution of muscle fatty infiltration in muscle imaging. Two other patients were classified as having a neurodevelopmental phenotype consisting in congenital or early onset, delay in motor milestones, and global developmental delay in one of them. Nerve conduction studies revealed an unequivocally axonal neuropathy with frequent spontaneous activity, and serum creatine kinase levels were increased in 50% of the patients. CONCLUSIONS: MORC2 mutations are a rare cause of CMT in Spain, but in-depth phenotyping reveals a recognizable phenotypic spectrum that will be clinically relevant for future identification of this disease.
BACKGROUND AND PURPOSE: MORC2 mutations have been described as a rare cause of axonal Charcot-Marie-Tooth disease (CMT2Z). The aim of this work was to determine the frequency and distribution of these mutations throughout Spain, to provide a comprehensive phenotypical description and, if possible, to establish a genotype-phenotype correlation. METHODS: Retrospectively, data on patients diagnosed with CMT2Z in Spain were collected and clinical, electrophysiological and muscle imaging information were analysed. RESULTS: Fifteen patients with CMT2Z were identified throughout Spain, seven of them belonging to a single kindred, whilst the rest were sporadic. The most common mutation was p.R252W, and four new mutations were identified. Eleven patients were categorized as having a scapuloperoneal phenotype, with asymmetric muscle weakness, early proximal upper limb involvement and frequent spontaneous muscular activity with distal sensory impairment and pes cavus, whilst two presented with a more classic length dependent sensory motor phenotype. This distinction was corroborated by the distribution of muscle fatty infiltration in muscle imaging. Two other patients were classified as having a neurodevelopmental phenotype consisting in congenital or early onset, delay in motor milestones, and global developmental delay in one of them. Nerve conduction studies revealed an unequivocally axonal neuropathy with frequent spontaneous activity, and serum creatine kinase levels were increased in 50% of the patients. CONCLUSIONS: MORC2 mutations are a rare cause of CMT in Spain, but in-depth phenotyping reveals a recognizable phenotypic spectrum that will be clinically relevant for future identification of this disease.